The objective of this research is to provide a better understanding of the factors that regulate automatic activity of normal and abnormal cardiac cells and how such behavior can be modified by different cardioactive agents. The major emphasis of research will be on sinus node and Purkinje fibers. It is hypothesized that disturbances of automaticity and/or conduction underlie most instances of sinus node dysfunction in man. This hypothesis will be evaluated using the techniques of rapid atrial pacing, premature atrial stimulation and drug infusion in an animal model of sinus node dysfunction. The relation between membrane potential and automatic behavior will be determined in isolated Purkinje fiber preparations. Techniques such as rapid stimulation and hypothermia will be employed to load the inside of the fiber with Na and the resulting hyperpolarization will be examined under control conditions and during exposure to selected cardioactive agents. Such studies will enable us to determine the mechanisms that underlie disturbances of rhythm in sinus node and in Purkinje fibers and the possible role of the Na pump in the regulation of cardiac automaticity and in the prevention of cardiac arrhythmias.